CS271498B2 - Method of new dihydropyridinamides production - Google Patents

Abstract

New compounds of the formula I, in which R<1> and R<8> means C1-6-alkyl, R<2> means C1-6-alkyl that can be in a strand interrupted by oxygen and can be substituted by C2-6-alkoxycarbonyl or phenyl, R<3> and R<4> means hydrogen or C1-4-alkoxy, R<5> means -O-(CH2)n-phenyl, -O-(CH2)n -pyridyl, -S-(CH2)n-phenyl or -O-SO2-phenyl, where n = 1 or 2 and phenyl can be substituted by the nitro group, CF3, C1-3-alky or halogen, R<6> and R<7> means hydrogen, C3-8-cykloalkyl, C1-12-alkyl or C2-5-alkenyl, which can be substituted by OH, C1-4-alkoxy, C2-5-alkylcarbonyl, phenyl, di-C1-4-alkylamino group, C3-6-cykloalkyl or pyridyl, they also mean phenyl, which can be substituted by the carbamoyl group, a acetyl amino group, or benzoylamino group or they mean the pyridyl group, as well as their physiologically utilizable salts are prepared via a reaction of aldehydes of the formula II and esters of β ketocarboxylic acid of the formula III with amides of β-ketocarboxylic acid of the formula IV with ammoniac, or in the presence of inert solvents and the acquired compounds are eventually converted to their physiologically utilizable salts. The produced compounds can be used in pharmaceuticals.<IMAGE>

Description

The present invention relates to a process for the production of novel dihydropyridinamides having valuable pharmacological properties, in particular the ability to affect blood circulation and can therefore be used as medicaments.

It is known that 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diethyl ester is obtained by reacting ethyl benzylideneacetic acid ethyl ester with ethyl aminocrotonic acid ester or ethyl acetate and ammonia / cf. E. Knoevenagel, Ber. Dtsch. Chem. Ges. 31, 743 (189).

It is further known that certain 1,4-dihydropyridines have interesting pharmacological properties (cf. F. Bossert, W. Vater, Natrurwissenschaften 58, 578 (1971)].

The present invention relates to a process for the preparation of the novel dihydropyridinamides of the formula I

(AND)

in which

R ¹

R ⁸

R ²

and

R ⁶

R ⁷ are the same or different from each other and are straight or branched (C 1 -C 6) alkyl, straight or branched (C 1 -C 6) alkyl optionally interrupted in the chain by an oxygen atom and optionally substituted by a 2-alkoxycarbonyl group up to 6 carbon atoms or a phenyl group, which are the same or different from one another and are hydrogen or C1-C4alkoxy,

-O- (CH ₂ ) _n -phenyl,

-O- (CH ₂ ) _n -pyridyl,

-S- (CH ₂ ) _n -phenyl or

-O-SO ₂ -phenyl in which n is 1 or 2 and the phenyl moiety is optionally substituted one to three times with nitro, trifluoromethyl, C 1 -C 3 alkyl or halogen, being the same or different from each other and

- hydrogen atom,

- C 3 -C 8 -cycloalkyl,

CS 271498 02

- a straight or branched alkyl group of up to 12 carbon atoms or an alkenyl group of up to 5 carbon atoms which may be optionally substituted by hydroxy, C1-C4alkoxy, C2-C5alkylcarbonyl, phenyl, dialkylamino, up to 4 carbon atoms in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl,

- a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or

a pyridyl group and their physiologically acceptable salts.

The compounds of formula (I) produced by the process of the invention exist in stereoisomeric forms, which behave either as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates to both antipodes and racemic forms as well as mixtures of diastereometers. Racemic forms can also be resolved as diastereomers in a known manner into stereoisomeric unitary components (cf. E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

Physiologically acceptable salts can be salts of compounds of formula I with inorganic or organic acids. Preferred are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.

Preferred are compounds of formula (I), which are the same or different from each other, and are straight or branched (C 1 -C 4) alkyl, straight or branched (C 1 -C 6) alkyl optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by phenyl, they are the same or different from each other and are hydrogen or C1-C4alkoxy,

-O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl, -S- (CH ₂ ) _n -phenyl or -O-SO ₂ -phenyl in which n is a number 1 or 2 and the phenyl moiety optionally substituted one to three times with nitro, trifluoromethyl, alkyl of 1 to 3 carbon atoms or fluorine, chlorine or bromine, being the same or different from each other and

- a hydrogen atom or a C 3 -C 7 cycloalkyl group,

- a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having up to 5 carbon atoms, which may optionally be substituted by hydroxy, C1-C4alkoxy, alkylcarbonyl

and

R ⁸

R ¹

R ²

R ³

R ⁵

R ⁶

R ⁴

R ⁷ is C 2 -C 5, phenyl, C 1 -C 4 dialkylamino in both alkyl moieties,

phenyl optionally substituted by acetylamino or benzoylamino, or

a pyridyl group and their physiologically acceptable salts.

Particularly preferred are compounds of formula I wherein я

R and R are the same or different and are methyl or ethyl,

R is a straight or branched (C 1 -C 6) alkyl group which is optionally interrupted in the chain by an oxygen atom and / or is optionally substituted by a phenyl group, R 3 and R 6 are the same or different and are hydrogen, methoxy or ethoxy,

R ⁵ represents -O-Cb ^ -phenyl, -O-Cl-pyridyl, -S-Cl ^ -phenyl or -0-S0 ₂ -phenyl, where the phenyl portion is optionally substituted up to twice by identical or different substituents selected from the group consisting of nitro, trifluoromethyl, methyl or fluorine or chlorine,

R @ 1 represents a hydrogen atom or an alkyl group of up to 4 carbon atoms;

R? means

a hydrogen atom, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, or

- a straight or branched alkyl group of up to 10 carbon atoms or an alkenyl group of up to 5 carbon atoms optionally substituted by hydroxy, C1-C4alkoxy, C1-C4alkylcarbonylalkyl, phenyl or dialkylamino C 1 -C 4 -alkyl;

R? means

phenyl optionally substituted by acetylamino or benzoylamino, or

Or a .gamma.-pyridyl group, and physiologically acceptable salts thereof.

R

According to the invention, the compounds of the formula I in which R and R have the meanings given above, and their physiologically acceptable salts, are prepared by reacting ketocarboxylic acid amides of the formula IV

(IV) wherein

7 8

R, R and R are as defined above, reacting with ammonia and ylidene / β-ketocarboxylic acid esters of the general formula

VIII

(VIII) wherein R ¹ , R ² , R ⁸ , R 6 and R 6 are as defined above, optionally in the presence of inert solvents, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts.

The process according to the invention can be illustrated by the following reaction scheme on a specific example of starting materials:

co-nh-c ₃ h ₇

O CH ₃

NH ₃

Suitable solvents for the reaction according to the invention are water or any inert organic solvents which do not change under the reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or amides, such as dimethylformamide, dimethylacetamide or hexamethyltriophosphoric triamide, or glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine. .

The reaction temperatures can be varied within a wide range. In general, temperatures between + 10 ° C and + 150 ° C are used, preferably at temperatures between + 20 ° C and +100 ° C. Particular preference is given to boiling the respective solvent.

The reaction can be carried out at atmospheric pressure, but also at elevated or reduced pressure. Generally, the process is carried out at atmospheric pressure.

The ratio of the starting materials involved in the reaction according to the invention is arbitrary. In general, however, molar amounts of reactants are used.

The isolation and purification of the compounds obtained by the process according to the invention is preferably carried out by distilling off the solvent under reduced pressure and recrystallizing the residue, if necessary only after cooling in ice, in a crystalline state from a suitable solvent. In some cases, it may be necessary to purify the compounds obtained by the process of the invention by chromatography.

The β-ketocarboxylic acid amides of the formula IV which are used as starting materials in the process according to the invention are known compounds or can be prepared according to known methods (cf., for example, 00S 11 42 859).

The ylidene / 3-ketocarboxylic acid esters of formula VIII, which are also used as starting materials in the process of the present invention, are known compounds or can be prepared according to known methods (cf., for example, G. Jones The Knoevenagel Condensation Organic Reactions, Vol. XV, p. 204 (1967)).

The compounds of formula (I) produced by the process of the present invention exhibit an unpredictable spectrum of valuable pharmacological effects. These compounds affect heart contractility, smooth muscle tone, as well as electrolyte and fluid levels.

Said compounds can be used in medicaments for the treatment of pathologically granular blood pressure and cardiac insufficiency, as well as as coronary therapeutics.

In addition, the compounds may be used to treat disorders of the heart rhythm, renal insufficiency, liver cirrhosis, ascites, pulmonary edema, brain edema, pregnancy edema, glaucoma or diabetes (Diabetes mellitus).

The activity of the compounds produced by the process of the invention on the activity of the heart was determined on isolated, stimulated papillary muscle of the guinea pig heart. To this end, the test animals (guinea pigs of both sexes weighing 200 g) are sacrificed, their chest is opened and the heart is removed. For the experiments, small papillary muscles are then removed from the right ventricle and fixed horizontally in the organ bath. Here, one end of the muscle is trapped between two metal electrodes, which simultaneously irritate the specimen, while the other end of the muscle is connected by a fiber to a force sensor. The papillary muscle is irritated at a frequency of 1 Hz above the threshold. The organ bath with a volume of about 2 ml was continuously washed with Krebs-Henseleit solution (in mmol concentrations: NaCl 118; Na ₂ C0 _3, 25; KC1 10; KH ₂ P0 ₄ 1.2, MgS0 ₄ 1.2, CaCl ₂ 1.8 glucose 10, pH 7.4) at 4 ml / min at 32 ° C. Papillary muscle contraction is measured isometrically through a connected force transducer and recorded using a recorder. ¹

The compounds of the invention are dissolved in Krebs-Henseleit solution at a concentration of 10 µg / ml, optionally using a co-solvent (dimethylsulfoxide up to 0.5%). The dihydropyridine carboxylic acid amides according to the invention exhibit a reduction in the papillary muscle contraction force by more than 10% relative to the values obtained in a control experiment.

CS 271498 82

The novel active compounds can be converted in a known manner into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. The therapeutically active compound is to be present in each case in a concentration of from about 0.5 to 90% by weight, based on the total mixture, i.e. in amounts which are sufficient to achieve the said dosage range.

The preparations are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with emulsifiers and / or dispersants, whereby organic solvents can be used as auxiliary solvents if water is used as the diluent.

Excipients which may be mentioned are, for example:

water, nontoxic organic solvents such as paraffinic hydrocarbons (e.g. petroleum fractions), vegetable oils (e.g. a mixture of peanut oil and sesame oil), alcohols (e.g. ethyl alcohol, glycerol), carriers such as natural stone flours (e.g. kaolins, alumina, talc) , chalk), synthetic stone meal (such as highly disperse silicic acid, silicates), sugars (such as cane sugar, milk sugar and grape sugar), emulsifiers (such as polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol polyesters, alkylsulfonates, arylsulfonates), detergents (e.g. lignin, sulfite waste liquors, methylcellulose, starches and polyvinylpyrrolidone) and glidants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in a conventional manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, the tablets may of course also contain, in addition to the aforementioned carriers, additives such as sodium citric acid, calcium carbonate and dicalcium phosphate together with various additives such as starches, preferably potato starch, gelatin and the like. stearic acid, sodium lauryl sulfate and talc, which are used as tableting aids. In the case of aqueous suspensions, in addition to the abovementioned excipients, various flavor enhancers or colorants can be added to the active compounds.

For parenteral administration, solutions of the active compounds using suitable liquid carriers can be used.

In general, it has proven advantageous to use an amount of from about 0.001 to 1 mg / kg, preferably from about 0.01 to 0.5 mg / kg body weight, for intravenous administration in order to achieve effective results. For oral administration, the dose is from about 0.01 to 20 mg / kg, preferably from 0.1 to 10 mg / kg of body weight.

However, in some cases, it may be necessary to deviate from the indicated amounts, depending on body weight, the mode of administration, the individual behavior of the medicament, the manner in which it is administered, and the time or interval at which it is administered. . Thus, in some cases it may be sufficient to use less than the minimum listed above, while in other cases the above upper limit must be exceeded. In the case of administration of larger amounts, it is advisable to divide this into several individual doses administered during the day.

In the following examples, R ^ values were determined on aluminum film for thin-layer chromatography (Merck), layer thickness 0.2 mm, silica gel 60 F 254; solvent system: a 1: 2 mixture of toluene and ethyl acetate.

Example 1

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-dimethylamide ____ _ _________________

g (6.45 mmol) of 2-benzyloxybenzylideneacetacetic acid methyl ester was heated to reflux with 0.83 g (6.45 mmol) of acetic acid dimethylamide and 0.53 ml of ammonia for 18 hours. The reaction mixture was then cooled and concentrated. The evaporation residue is taken up in ethyl acetate, the ethyl acetate solution is shaken twice with water, dried and concentrated. The mixed product was purified by silica gel column chromatography using a mixture of toluene and ethyl acetate as eluent. The pure fractions were collected and then concentrated. The product crystallized upon trituration with ether and a small amount of ethyl acetate. The product obtained is filtered off. 0.6 g (22.9% of theory) of a colorless substance is obtained. _Rf value = 0.118.

Example 2

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide ______

3.1 g (10 mmol) of 2-benzyloxybenzylideneacetacetic acid methyl ester are boiled with 1.4 g (10 mmol) of acetoacetic acid cyclopropylamide and 0.95 g of ammonium acetate for 5 hours in 30 ml of isopropyl alcohol. The reaction mixture was concentrated and the residue was purified over a silica gel column using toluene / ethyl acetate as eluent. The pure fractions are concentrated, the residue is stirred with acetonitrile, the product is filtered off and washed with acetonitrile. 0.7 g of colorless crystals of melting point 194 DEG C. are obtained.

In an analogous manner to that described in Examples 1 and 2, the compounds shown in the following Examples were also prepared.

Example 3

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-phenylamide

Mp 194 ° C.

Example 4

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point 156-157 ° C.

Example 5

1,4-Dihydro-2,6-dimethyl-4- (2- (3-methylbenzyloxy) phenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Melting point 176 ° C.

Example 6

4- [2- (4-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Melting point 178 ° C.

Example 7

4- [2- (4-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-pyridyl) amide

Mp 201-204 ° C.

Example 8

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-pyridyl) amide

N H

Melting point 164-165 ° C.

Example 9

4- [2- (4-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-diethylaminoethyl) amide

Melting point: from 80 ° C.

Example 10

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-diethylaminoethyl) amide. acid

Melting point: 95 ° C.

Example 11

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-carbamoylphenyl) amide;

conh ₂

Melting point above 300 ° C.

Example 12

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5- (4-acetylaminophenyl) amide.

Mp 298 ° C (dec.).

Example 13

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-ester-5- (4-benzoylaminophenyl) amide

Melting point 197 ° C.

Example 14

(R, S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-demethyl pyridine-3,5-dicarboxylic acid 3-methyl ester 5- (1-phenylethyl) amide (mixture of R, S) ) _________ __

Melting point: from 162 ° C.

Example 15

(R) -4- (2-Benzyloxy-phenyl (-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid) -R-form) - 3-methyl-estrogen-5- (1-phenylethyl) -amide

Melting point 82 ° C.

Example 16 ’

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-dimethylaminopropyl) amide

Mp 89-90 ° C.

Example 17

4- (2-Benzyloxyphenyl (-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid) 3-methyl ester-5-cyclohexylamide)

Melting point 108-111 ° C.

CS 271498 02

Example 18

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-tert-butylamide h ₃ cooc h ₃ c

Mp 148 ° C.

Example 19

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-propylamide

Foam, R _f = 0.37.

Example 20

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide

Melting point 134 ° C.

Example 21

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-N-benzyl-N-tert-butylamide

Melting point 128 ° C.

Example 22

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point 105 ° C.

Example 23

4- (2-Benzyloxyphenyl (-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid) 3-methyl ester-5-ethylamide)

Example 24

1,4-Dihydro-2,6-dimethyl-4- [2 - (- pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide

Foam, Rf = 0.1.

Example 25

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-methylamide _______ ________

Foam, R _f = 0.07.

Example 26

1,4-dihydro-2,6-dimethyl-4- [2- (2-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-methylpropyl) amide

Foam, Rf = 0.25.

CS 271499 B2

Example 27

4- [2- (3,4-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropyl-amide

Mp 195 ° C.

Example 28

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Cl

Melting point 178 ° C.

Example 29

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-methyl-propyl) -amide

H 2 COOC h ₃ c

Foam, R _f = 0.36.

Example 30

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide ___ ___ ____ ____

Melting point 133 ° C.

Example 31

4- [2- (3,4-Dichlorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide ________

Melting point 120 ° C.

Example 32

4-Q2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide __________ ________

Melting point 202 ° C.

Example 33

4- [2- (2-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-3-methyl-5-cyclopropylamide

Mp 185 ° C.

Example 34

4- [2- (2-Chloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide.

Melting point 170 ° C.

Example 35

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide

Melting point 98 ° C.

Example 36

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Mp 148 ° C.

Example 37

1,4-Dihydro-2,6-dimethyl-4- [2- (3-trifluoromethyl-benzyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-methyl-propyl) -amide

Foam, Rf = 0.44.

Example 38

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-isopropylamide

Melting point 106 ° C.

Example 39

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-cyclopropylamide

Foam, R _f = 0.31.

Example 40

4- (Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Melting point 197 ° C.

Example 41

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenol] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5- (1-methylpropyl) amide

H

Melting point 126 ° C.

Example 42

1,4-Dihydro-2,6-diethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3- (1-methylpropyl) ester-5-methylamide

Foam, R _f = 0.48.

Example 43

1,4-Dihydro-2,6-dimethyl-4- [2- (3-nitrobenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide

Foam = 0.24.

Example 44

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-fluoro-amide

Melting point 210 ° C;

CS 271498 В2

Example 45

(R) -4- [2- (4-Fluoro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenylethyl) -amide (R) -form)

Foam, R _f = 0.56.

Example 46

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-methylpropyl) amide

Melting point 202 ° C.

Example 47

4- [2- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-cyclopropylamide

Mp 159 ° C.

Example 48

4- [2- (4-Fluoro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-ester-5-cyclopropylamide

Melting point 154 ° C.

Example 49

(S) -4- (4-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenyl-ethyl) -amide (S-form)

Melting point 141 ° C.

Example 50

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-1sopropylamide

Melting point 162 ° C.

Example 51

(R) -4- (4-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenylethyl) -amide (R-form, diastereomer A) )

Example 52

4- [2- (3-Chlorobenzyloxy) -phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide h ₃ cooc h ₃ c

Melting point 174 ° C.

Example 53

4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester -5-cyclopropylamide

AND

Melting point 202 ° C.

25,

CS 27149В B2

Example 54

(R) -4- (4-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) -amide (diastereomer B) (R-form) )

Example 55

(R) -4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide (R-form, diastereomeric mixture)

Example 56

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenyl-ethyl) -amide (S-form, diastereomer A)

Example 57

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-ester-5- (1-phenylethyl) -amide (S-form, diastereomer B)

Example 58

(R) -4- [2- (4-Fluorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenylethyl) amide form)

Foam, Rf = 0.52.

Example 59

1,4-Dihydro-2,6-dimethyl-4- [2- (3-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-butyl ester-5-cyclopropylamide

2Ί

CS 271498 Β2

Example 60

(R) -1,4-Dihydro-2,6-dimethyl-4- [2- (3-methyl-benzyloxy) -phenyl} -pyridine-3,5-dicarboxylic acid 3-butyl ester-5- (1-phenyl-ethyl) -amide

Oil, Rf = 0.88,

Example 61

(R) -4- [2- (3-Chloro-benzyloxy) -phenyl} -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenyl-ethyl) -amide form)

Foam, R _f = 0.73.

Example 62

(R) -4- (3-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenyl-ethyl) -amide (R-form)

Mp 143 ° C.

Example 63

4- (3-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Mp 144 ° C.

Example 64

(R) -4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-ester-5- (1-phenylethyl) amide form)

Foam, _Rf = 0.47.

Example 65

(S) -4- [2- (4-Fluoro-benzylthio) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-phenyl-ethyl) -amide (S-form) )

Foam, Rt &lt; 0.48,

CS 271498 82

Example 66

4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid J-methyl ester-5-allylamide

co-nh-ch ₂ -ch = ch ₂

CH 2

Melting point 177 ° C.

Example 67

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

148 ° C,

Example 68

(R) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-demithyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-phenylethyl) -amide (R-forma)

Melting point 175 ° C.

Example 69

(R) -N- (2-Benzyloxyphenyl) -1D-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid (R-form, diastereomer B) )

Melting point 169 ° C.

Example 70

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-Lestec-5- (2-phenylethylamide)

Oil.

Example 71

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-5-benzylamide

Melting point 140-149 ° C.

Example 72

4- [2- (4-Fluorobenzylthio) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3-methyl ester-5-ethylamide

Mp 202-204 ° C.

Example 73

Boxylic acid 3-methyl ester-5-ethyl amide

4- (3-benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicar-

Mp 152-154 ° C.

Example 74

4- (4-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicar- 3-methyl ester-5-ethylamide

'•'

CS 271498 В2

Example 75

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-amide

Mp 188 ° C.

Example 76

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-diethylamide

Melting point 135 ° C.

Example 77

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid J-methyl ester-5-cyclopropylamide »

Mp 238-242 ° C.

CS 271498 82

Example 78

1,4-dlhydro-2,6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Melting point 22 ° C.

Example 79

4- [4- (2,6-dichlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide _______

Melting point 174-176 ° C.

Example 80

4- [2- (3,4-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Melting point: 178-180 ° C.

CS 271490 02

Example 81

1,4-Dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) phenyl] pyridine-3-methyl ester-5-ethylamide

3,5-dicarboxylic acids

M.p. 159-161 ° C.

Example 02

3-Methyl-tert-5-cyclopropyl-1,4-dihydro-2,6-dimethyl-4- [2- (2-pyridylmethyloxy) -phenyl] -pyridine-3,5-dicarboxylic acid

Melting point 160-170 ° C.

Example 83

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point 171-173 ° C.

Example 84

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-methyl ester-5-ethylamide

-dicarboxylic acids

Mp 188-190 ° C.

Example 85

1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-dimethylpiridine- 3-ethyl-5-ethylamide

3,5-dicarboxylic acids

Mp 147-149 ° C.

Example 86

1,4-Dihydro-4- [2- (4-fluorobenzyloxy) phenyl] -2,6-dimethylpyridine-3-methyl ester-5-ethylamide-

3,5-dicarboxylic acids

Melting point 111-113 ° C.

CS 271490 02

Example 07

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

M.p. 154-156 ° C.

Example 08

1,4-Dihydro-2,6-dimethyl-4- (2-phenylsulfonyloxyphenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (4-pyridyl) amide

Melting point: 240 DEG C. (decomposition).

Example 1 a d 8 9

4 - [- (4-Chlorobenzyloxy) phenyl] -1,4-dihydro-2,6-dimethylpyridine- 3-methyl ester-5-allylamide

3,5-dicarboxylic acids

Melting point 145 ⁰ C.

Example 90

3-Methyl-5-xylic acid allylamide 4- (3-benzoyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarbo

Melting point 95-9 ° C.

Example 91

3-methyl-5-allyl _amide) is _{4-dihydro-2H-l} 6-dimethyl-4- [2- (4-methylphenylsulfonyloxy) phenyl] pyridine-3,5-dicarboxylic acid

Melting point 160-170 ° C.

Example 92

4- [2- (2,6-Dichloro-benzyloxy) -phenyl] -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5-allylamide

M.p. 132-134 ° C.

'' IW

CS 271498 82

Example 93

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-hydroxyethyl) amide

M.p. 148-150 ° C.

Example 94

4- [2- (3-Fluorobenzyloxy) -3-methoxyphenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point 171-173 ° C.

Example 95

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5 - [] 2- (4-pyridyl) ethyl] amide

N H

CS 27149В B2

Example 96

1,4-Dihydro-2,6-dimethyl-4- [2- (3-pycidyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point: 210 ° C.

Example 97

1,4-Dihydro-2,6-dimethyl-4- [2- (3-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Mp 122-125 ° C,

Example 98

1,4-Dihydro-2,6-dimethyl-4- [2- (4-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

H

Melting point 95-100 ° C,

Example 99

1,4-Dihydro-2,6-dimethyl-4- [2- (4-pyridyl) methoxyphenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methylamide

Melting point: 203 DEG C. (decomposition).

Example 100

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (cyclopropylmethyl) amide

Melting point 186 ° C.

Example 101

(+) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Melting point 147 ° C.

+ 29.68, c =

0.91 (DMF).

Example 102

(-) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethyl amide

Mp 148 ° C.

[.Alpha.] _D @ ²⁰ = -29.92 DEG, c = 0.805 (DMF).

Example 103

4- (2-Bezyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methylamide

Mp 179 ° C.

Example 104

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-ethyl ester-5-ethylamide

Mp 161-164 ° C.

Example 105

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2-ethoxycarbonylethyl) amide

R _f = 0.35.

Example 106

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (ethoxycarbonylmethyl) amide

R _f = 0.408.

Example 107

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-octylamide <

0.53.

Example 10В

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-nonylamide

R _f = 0.55.

Example 109

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-decylamide

Melting point 111 ° C.

Example 110

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-ester-5- (2-methoxyethyl) amide

145 ° C.

Example 111

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl-estrogen-5- (3-methoxypropyl) -amide

R _f = 0.19.

Example 112

(R, R) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine <-3,5-methyl-5- (2-hydroxy-1-methyl-2-phenyl) ethylamide -dicarboxylic acids

R _f = 0.35

[.Alpha.] D @ ²⁰ = -47.93 DEG (in chloroform).

Example 113

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (2-hydroxy-1-methyl-ethyl) -amide

R _f = 0.13

Wq °: + 7.34 ° (CHCl ₃ ).

CS 271498 82

Example 114

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-propyl) -amide

R _f = 0.15 [<3о ° '- ^{9>' 7} ° (CHCl₃).

Example 115

(S) -4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (1-hydroxymethyl-2-methylprapyl) amide

R _f = 0.19

Θ °: - 10.8 ° (CHCl 3).

Example 116

(S) -4- (2-Benzyloxy-phenyl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid 3-methyl-5- (1-hydroxymethyl-2-methyl-butyl) -amide

R _f = 0.21

[Α] D = -17.37 ° (CHCl 3).

CS 271498 82

Example 117

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (3-hydroxypropyl) amide

Mp 205 ° C.

Example 118

(-) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Mp 178-181 ° C; [V] ₅ g9 _ 38.28 (c = 0.569, chloroform).

Example 119

(+) - 4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-cyclopropylamide

Melting point: 178-181 ° C

M? ₉ ° = + 36.56 ° (c = 0.52, chloroform).

CS 271491 B2

Example 120

4- (2-Benzyloxyphenyl) -1,4-dihynro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-hexylamine

Melting point 133 ° C.

Example 121

3-methyl-5-4- [2- (4-methylbenzensulfonyloxy) -phenyl 1J - l, 4- ^d benzonitrile-2,6-dimethylpyridine-3,5-dicarboxylic acid

Mp 205 ° C.

Example 122

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-sec butylamide

Melting point 135 ° C.

Example 123

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-amide

Mp 190 ° C.

Example 124

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl ester) -5-amide

Melting point 165 ° C.

Example 125

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5-butylamide

• N H

Example 126

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-ethylamide

Example 127

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyrrole-5- (3-ethoxypropyl) amide 3-methyl ester

Melting point 115 ° C.

Example 128

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-methyl ester-5- (5-hydroxypentyl) amide

Melting point 178 ° C.

* fVs.

Example 129

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5-methyl amide

M.p. 133-135 ° C.

Example 130

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-methoxyethyl) ester-5-ethylamide

Melting point 111 ° C.

Example 131

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-methyl-amide

Melting point 140-143 ° C.

CS 271491 B2

Example 132

3- i op op op op-les tur-5-сук 1 op rapy lunild 4- (2-Penzyloxyphenyl) -1,4- and ihydro-2,6-dl thy 1 μ rld ln-3, 5-dicarboxylic acids

M.p. 132-135 ° C.

Example 133

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-isopropylamide

Melting point up to 110 ° C.

Example 134

1,4-Dihydro-2,6-dimethyl-4- (2- (4-methylbenzyloxy) phenyl) pyridine-3,5-dicarboxylic acid 3-methyl ester-5-ethylamide

Melting point 184 ° C.

CS 271498 82

Example 135

1,4-Dihydro-2,6-dimethyl-4- [2- (4-methylbenzyloxy) phenyl] pyridine-3,5-dicarboxylic acid 3-methyl ester-5-methyl amide

Melting point 186 ° C.

Example 136

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (S) - (1-isopropoxycarbonylethyl) ester-5-cyclopropylamide

Example 137

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenyl) ester-5-methylamide

Example 13Θ

4- (2-Benzyolxyphenyl) -1,4-thihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-propylamide

Example 139

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylic acid 3- (2-phenethyl) ester-5-cyclopropylamide

m.p. 152 [deg.] C.

Example 140

4- (2-Benzyloxyphenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicago boxylic acid 3-methyl ester-5-octylamide

Rf = 0.44 in toluene / ethyl acetate 1: 1

Claims (4)

A process for the preparation of the novel dihydropyridinamides of the general formula I in which R ^1a are the same or different from each other and are a straight or branched (C 1 -C 6) alkyl group; R is a straight or branched (C 1 -C 6) alkyl group optionally interrupted in the chain by an oxygen atom and optionally substituted by a (C 2 -C 6) alkoxycarbonyl or phenyl group, and R ⁴ are the same or different from each other and are hydrogen or (C 1 -C 4) alkoxy represents -O- (CH ₂ ) _n -phenyl, -O- (CH ₂ ) _n -pyridyl. -S- (CH ₂ ) _n "phenyl or -O-SO ₂ -phenyl in which n is 1 or 2a the phenyl moiety is optionally substituted one to three times by nitro, trifluoromethyl, C 1 -C 3 alkyl or a halogen atom, are the same or different from each other and are - hydrogen atom, - C 3 -C 8 -cycloalkyl, - a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having up to 5 carbon atoms, which may optionally be substituted by a hydroxy group, a C1-4 alkoxy group, a C2-5 alkylcarbonyl group, a phenyl group, a 1-dlalkylamino group up to 4 carbon atoms in both alkyl moieties, C 3 -C 6 cycloalkyl or pyridyl, - a phenyl group which is optionally substituted by carbamoyl, acetylamino or benzoylamino, or - a pyridyl group as well as their physiologically acceptable salts, characterized in that the β-ketocarboxylic acid amides of the general formula IV (IV) in which R, R and R are as defined above, reacting with ammonia and ylidene-X3-ketocarboxylic acid esters of the general formula VIII (VIII) in which R ¹ , R ² , R ⁴ , R ⁴ and R ⁵ are as defined above, optionally in the presence of inert solvents, whereupon the compounds obtained are optionally converted into their physiologically acceptable salts. 2. Process according to claim 1, characterized in that water and internal organic solvents such as alcohols, ethers, amides, glacial acetic acid, dimethylsulfoxide, acetonitrile or pyridine are used as solvents and the reaction is carried out at temperatures between 10 and 150 ° C. . 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the general formulas (IV) and (VIII) are used as starting materials to give compounds of the general formula (I) in which: 1 8 R and R are the same or different from each other and represent a straight or branched (C 1 -C 4) alkyl group, R is a straight or branched (C 1 -C 6) alkyl group optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group, 3 4 R and R are the same or different from each other and are hydrogen or (C1-C4) alkoxy, -O- (CH3) _n- ene-1-group, -O- (CH 2) _{r -} -Pyrisyl, -S- (CH 2) _n -flyl or -SO 2 -phenyl wherein n is 1 or 2 and the phenyl moiety is optionally substituted one to three times by fluorine, chlorine, a bromine atom, a nitro group, a trifluoromethyl group or a C 1 -C 3 alkyl group, R ^ and R? they are the same or different from each other and mean - a hydrogen atom or a C 3 -C 7 cycloalkyl group, - a straight or branched alkyl group having up to 12 carbon atoms or an alkenyl group having up to 5 carbon atoms, which may optionally be substituted by a hydroxy group, a C1-C4 alkoxy group, a C2-C5 alkylcarbonyl group, a phenyl group, a 1-dialkylamino group up to 4 carbon atoms in both alkyl moieties, phenyl optionally substituted by acetylamino or benzoylamino, or - the pyridyl group and their physiologically acceptable salts. 4. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas IV and VIII are used as starting materials to give compounds of the formula I in which: 1 8 R and R are the same or different and are methyl or ethyl, R is a straight or branched (C 1 -C 6) alkyl group optionally interrupted in the chain by an oxygen atom and / or optionally substituted by a phenyl group, R ⁵ and R 6 are the same or different and are hydrogen, methoxy or ethoxy, R ⁵ represents -O-C 1-4 -phenyl, -O-C 1-4 -pyridil, -S-C 1-4 -phenyl or -O-Si-phenyl, the phenyl moiety optionally being up to twice substituted by the same or different substituents selected from the group consisting of fluorine, chlorine, nitro, trifluoromethyl or methyl are hydrogen or C1-C4 alkyl; and R 6 represents a hydrogen atom, a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, or - a straight or branched alkyl group having up to 10 carbon atoms or an alkenyl group having up to 5 carbon atoms optionally substituted by hydroxy, C1-C4alkoxy, C1-C4alkylcarbonyl in the alkyl moiety, phenyl or dialky a (C 1 -C 4) -alkylene group; CS 271491 B2 phenyl optionally substituted by acetylamino or benzoylamino, or - a β 3 or -pyridyl group, and physiologically acceptable salts thereof.